Neuroendocrine Theory of Aging: Chapter 1

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Introduction

Ward Dean, MD

The Neuroendocrine Theory of Aging was first described in 1954 in a Master’s Thesis by the distinguished Russian gerontologist, Vladimir Dilman, M.D., Ph.D., D.M.Sc.(1) Although Dilman was very well known in Russia as a scientist and popular author, he was practically unknown outside of Eastern Europe because most of his books and articles were only available in Russian. In 1981, two years prior to the publication of the blockbuster, Life Extension (2.5 million copies published), one of Dilman’s books was translated into English in a short press run of about 1,000 copies.(2)

I happened to be fortunate enough to obtain several copies of this book, and in 1983 began corresponding with Dilman. In 1992 we coauthored an updated version of his theory in our book, The Neuroendocrine Theory of Aging and Degenerative Disease.(3) Unfortunately, our book sold out almost immediately, and I’ve never had time to reprint it. From 1999 through 2003, a simplified and updated version of Dilman’s innovative theory was serialized in Vitamin Research News. Since many of my readers missed those early issues, I am revising and reprinting the entire series here.

Dilman’s theory, in essence, is that aging is primarily caused by a progressive loss of receptor sensitivity of the hypothalamus (and related structures in the brain) to negative feedback inhibition. While this loss of sensitivity is essential for normal growth and development, it is also the cause of post-maturational diseases, aging and death.

The Neuroendocrine Theory explains the cause of the major diseases of aging, which contribute to over 85 percent of deaths and disabilities of middle-aged and elderly individuals. These diseases include: obesity, atherosclerosis, hypertension, diabetes, cancer, autoimmune disorders, metabolic immunodepression, and hyperadaptosis. Two other diseases — depression and menopause — although not fatal, also occur regularly with age. (Menopause is included by Dilman as a disease, because he describes disease as “any permanent violation of internal constancy.”)

Several of these diseases (hyperadaptosis, and metabolic immunodepression) have strange-sounding names, but as one gains an understanding of Dilman’s theory, these names will become more familiar.

Endocrine System

To understand Dilman’s concepts, it helps to have a “working knowledge” of the endocrine system (Fig. 1). Although the pituitary gland in the brain directs the activities of the endocrine system, the pituitary is itself controlled by another structure in the brain, called the hypothalamus.

Substances known as “releasing factors” trickle down from the hypothalamus to the nearby pituitary and activate the release of one or more of its hormones. These hormones, in turn, stimulate the production of hormones in other glands (i.e., the thyroid, the adrenals, the testes, the ovaries and the thymus).

Homeostasis

A basic principle in physiology is the concept of homeostasis. Homeostasis is the state of maintaining the body’s physiological, endocrine and biochemical parameters within a fairly narrow range to support health and life. The homeostatic ranges required by the body are relatively narrow, and if any critical parameter above or below “normal” (i.e., blood pressure, blood sugar, or body temperature), it is considered a disease.

Common examples of homeostatic systems include thermostats used to control the temperature in our homes, or floats controlling water levels in a toilet tank.

A finely-tuned thermostat will maintain your home at a narrowly-defined, comfortable temperature. However, as the thermostat wears out and loses sensitivity, the house temperature is more varied and uncomfortable since the thermostat does not kick on and off as it should. Likewise, a poorly functioning toilet tank float can result in either too little water in the tank to flush adequately, or the water may overflow or never stop running.

Hypothalamus and Homeostasis

The hypothalamus is the body’s primary organ of homeostasis, responsible for maintaining the equilibrium of most biological processes within a fairly narrow range.

For the hypothalamus to do this, it must be sensitive to biochemical changes indicating slight deviations in these functions. Too much or too little of a particular hormone in the tissues causes the hypothalamus to secrete greater or lesser amounts of specific releasing factors and/or inhibiting factors to bring about the necessary adjustment.

The hormones released from the hypothalamus, in turn, cause the pituitary gland to release stimulating hormones. These stimulating hormones cause the peripheral endocrine glands (thyroid, adrenals, ovaries and testes) to secrete “their” hormones (thyroxine, cortisone, estrogen, progesterone, and testosterone, to name a few).

In this fashion, this system is controlled by negative feedback—i.e., as the blood level of a peripheral hormone (like thyroxin or testosterone) rises, it causes feedback to the hypothalamus and pituitary, signaling them to reduce their output of stimulatory releasing factors and hormones (Fig. 2).

Pineal Gland

Recent research indicates that the hypothalamus is itself influenced by another structure in the brain known as the pineal gland. The pineal gland is responsible for the regular cyclical functioning of the entire neuroendocrine system, most notably our 24-hour sleep-wake cycle, as well as many other chronobiological functions.

For example, jet lag can be attributed to pineal gland dysregulation. Jet lag is commonly experienced by travelers (particularly when traveling in an easterly direction), but can also be caused by sleep dysregulation from performing shift work, or just staying out too late at night. As we grow older, we are less able to tolerate changes in our sleep-wake cycle, and the symptoms of “jet lag” become progressively worse due to a decrease in the output of melatonin, the principle hormone of the pineal gland.

Many older people have difficulty sleeping at night, and, as a result, experience fatigue during the day. Usually this is accompanied by a constellation of other symptoms, including memory loss, irritability, confusion, depression or constipation. These symptoms are similar to those of jet lag. Consequently, I believe many people who suffer from these symptoms are actually suffering from aging-induced, chronic chronobiological desynchronization, which, like jet lag, is caused by depressed levels of melatonin (Fig. 3).

Homeostasis and Aging

If our bodies were able to remain in perfect homeostasis from birth, further growth and development would not take place. Dilman believed that the shift of hypothalamic sensitivity to negative feedback is the mechanism that enables growth and development to occur.

However, it is also a primary mechanism of aging and the diseases of aging. For example, in an infant, only minute amounts of testosterone are produced. If our bodies truly maintained a state of homeostasis, even these small amounts of hormone would be adequate to prevent the hypothalamus and pituitary from producing greater amounts of testosterone-stimulating releasing factors and hormones.

If this were the case (not only with testosterone, but with all hormones), growth and development would never occur, and we would remain infants throughout our lives. Thus, throughout childhood and puberty, there is a constant shifting of homeostasis, resulting in growth and development.

The problem is that once we have reached adulthood, there is no mechanism to shut off this progressive loss of hypothalamic sensitivity to feedback inhibition. Thus, the homeostatic balance—which appears to reach its optimum at ages 20 to 25—continues to shift, resulting in more (i.e., cortisol, insulin) or less than optimum (i.e., estrogen, testosterone) levels of many hormones, and ultimately, the exhaustion of the peripheral endocrine glands due to their prolonged efforts to overcome the loss of hypothalamic sensitivity.

Hypothalamic Threshold

What causes the loss of receptor sensitivity with age? This is not known for certain, but Dilman identified the following possible factors:

Reduced quantity of hypothalamic hormone receptors (which may be caused partially by the drop in biogenic amine concentrations);

Decline in the secretion of pineal gland hormones (melatonin and pineal polypeptide hormones);

Fat accumulation; reduced glucose utilization;

Accumulation of neuronal lesions produced by chronically elevated levels of cortisol due to prolonged stress;

Accumulation of cholesterol in plasma membranes of neurons.(4)

Homeostats and Growth

Dilman believed that the three homeostatic systems (which he designated, “homeostats”) involved in growth, development and aging are:

The adaptive (hypothalamic-pituitary-adrenal axis);

The reproductive (hypothalamic-pituitary-gonadal axis), and;

The energy (hypothalamic-pituitary-thyroid axis) homeostats.

I believe that another homeostat should be added to these three — the immune (pineal-hypothalamic-pituitary-thymus) homeostat.

It is the breakdown or alteration in the functioning of these homeostats that causes the metabolic changes that characterize aging and the diseases of aging. Dilman intuitively determined that all of the diseases of aging are characterized by similar metabolic changes. The most prevalent of these changes include the reduction in glucose tolerance, hyperinsulinemia and hyperlipidemia.

Dilman’s theory provides a bold new theoretical foundation for the aging process itself, as well as concrete, clinically tested protocols for the treatment and prevention of the diseases of aging. The beauty of this theory is that it neither contradicts other, more established theories of aging, nor is it mutually exclusive. Rather, it either incorporates or supplements other theories.